Androgen is a term used to identify the human male sex hormones. These hormones, which are chemically classified as steroids, are produced in the body by the testis, the cortex of the adrenal gland and, to a much lesser extent, by the ovaries. Testosterone is perhaps the most widely recognized androgen, and is responsible for the development of male characteristics in a human, including secondary sexual characteristics, libido and the ability to produce sperm.
When a person is unable to synthesize testosterone, therapy directed at replacing the missing hormone is commonly undertaken. In practice, however, this therapy can be problematic. For example, testosterone exhibits only weak activity when administered orally. While parenteral administration is possible, it is impractical because testosterone remains active in the body for only a short time. Research has therefore focused on identifying so-called synthetic androgens that are acceptable substitutes for natural testosterone.
A number of oral and injectable synthetic androgens have been developed over the years, including esters of various androgens. While these esters are hydrolyzed in the body into their corresponding biologically-active alcohols, they are nonetheless administered because they slow the rapid degradation of the synthetic androgen by the body. This maximizes the amount of the biologically active alcohol that reaches the bloodstream.
Unfortunately, the activity of these androgen esters is unpredictable. Different androgens sharing the same ester group exhibit varying and unpredictable levels of activity, as do androgens having the same basic chemical structure, but different ester groups.
One of the esters that has emerged as a viable injectable synthetic androgen is testosterone enanthate. This enanthate is presently used extensively via intramuscular (IM) injection for hormone replacement therapy in hypogonadal men, and as the androgenic component of several experimental male contraceptives. One drawback of this active is that it is not exceptionally long-acting—it must be administered IM every two weeks to maintain testosterone levels within a normal (therapeutic) range in hypogonadal men.
More specifically, testosterone enanthate is presently administered IM for the treatment of hypogonadism at a dose of 200 mg every two or three weeks. If this enanthate is used for male contraception, it may be administered parenterally at from about 200-400 mg every week, and if used as the androgenic component with estrogen or progestins for contraception, it may be administered at about 200 mg every two weeks. Testosterone bucyclate is another synthetic androgen disclosed in, e.g., U.S. Pat. No. 4,948,790. If administered parenterally for the treatment of hypogonadism, this bucyclate would require a dose of about 1200 mg (given as 3 injections of 1 ml each due to its solubility) to retain activity for about 2-3 months.
The development of androgens that exhibit activity after oral administration has been less successful. At present, the most widely used effective oral formulation includes methyltestosterone as the active ingredient, administered at 10-50 mg methyltestosterone/day. However, this active cannot be administered on a long-term basis, as is required in androgen replacement therapy, because of its associated liver toxicity. It is well known that androgens alkylated at the C17 position, such as methyltestosterone, exhibit such toxicity. While removal of the C17 alkyl group may appear at first glance to be an obvious solution to this problem, alkylation at this position is believed to be necessary to prevent degradation of the active by the liver after oral administration.
Illustrative of the development efforts relating to synthetic androgens is U.S. Pat. No. 5,952,319. While this patent identifies a number of potentially-active synthetic androgens, including 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one 17β-trans-4-n-butylcyclohexane carboxylate (referred to herein as 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate), it provides no data regarding the biological activity of 7α,11β-dimethyl-17β-hydroxy-4-estren-3-one bucyclate. There is similarly no data available concerning the biological activity of another synthetic androgen, 7α,11β-dimethyl-17β-hydroxyestr-4-en-3-one 17-undecanoate.
A need therefore exists for a means of overcoming the foregoing and other problems associated with androgen replacement and other therapies that require the administration of androgens.